CN109761988B - Preparation method of sitagliptin serving as medicine for treating diabetes - Google Patents

Abstract

The invention provides a method for preparing sitagliptin with a shorter route, which comprises the steps of obtaining a chiral amine compound by reductive amination of borohydride in the presence of a chiral ligand, activating carboxyl by N-hydroxysuccinimide, reducing side reactions, obtaining a high-yield and high-purity sitagliptin product, wherein reaction raw materials are cheap and easy to obtain, the reaction process is easy to operate, the yield of each step is high, the product purity is high, the production cost is reduced, and the method is favorable for industrial production.

Description

Preparation method of sitagliptin serving as medicine for treating diabetes

Technical Field

The application relates to a preparation method of a medicine sitagliptin for treating diabetes, belonging to the field of western medicine synthesis.

Background

The incidence of diabetes has been increasing year by year in recent years, and diabetes has become a non-infectious disease which seriously threatens human health after cardiovascular disease malignant tumor. The incidence rate of type II diabetes is 90%, and the pathogenesis of type II diabetes is mainly caused by the resistance of human body to insulin and the functional defect of insulin and cells. Clinically used for treating type II diabetes mainly comprises insulin secretion promoters, sulfonylureas, meglitinides, insulin sensitizers, insulin and insulin receptor agonists and dipeptidyl peptidase-4 inhibitors.

Sitagliptin is the first dipeptidyl peptidase-4 inhibitor developed by Merck Sharp & Dohme Ltd company, which was marketed in us 10 months 2006. Sitagliptin is a dipeptidyl peptidase-4 inhibitor, inhibits the activity of the DPP-4 active part through the combination of an amide part and the DPP-4 active part, prolongs the half-life of the hypoglycemic Incretin, improves the activities of GLP-1 and GIP in plasma, only slightly increases the content of the GLP-1 and GIP, does not cause side effects caused by overhigh content of GLP-1, and has better safety and tolerance. Compared with similar medicines, the sitagliptin has outstanding medication advantages, and has better research value based on good market prospect.

Sitagliptin, known by the Chinese cultural name of (2R) -4-oxo-4- [3- (trifluoromethyl) -5, 6-dihydro [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl ] -1- (2,4,5-trifluorophenyl) -2-amine, known by the English name of (3R) -3-Amino-1- [3- (trifluoromethyl) -5,6,7,8-tetrahydro-l,2,4-triazolo [4,3-a ] pyrazine-7-yl ] -4- (2,4, 5-trifluoromethylphenyl) butan-l-one, has the chemical structural formula shown in the specification, the molecular weight of 407.32 and the molecular formula of C16H15F6N 5O.

In recent years, the demand for the drug administration of sitagliptin is increased, and the preparation technology of the sitagliptin is receiving wide attention. At present, the synthesis method of sitagliptin is mainly chemical synthesis method.

The first-generation synthetic route for the industrial production of sitagliptin is a chemical synthetic route which is catalyzed and synthesized by Hansen et al by adopting a chiral ruthenium phosphide catalyst. The reaction route is that 4-2,4, 5-trifluorophenyl-3-oxo methyl butyrate is catalyzed by a chiral metal catalyst S-binaphthyl diphenyl phosphine-ruthenium chloride for asymmetric hydrogenation, then hydrolyzed in methanol solution of sodium hydroxide to obtain hydrolysate, condensed with O-benzyl hydroxylamine under the action of N-ethyl-N-dimethylamino propylamine carbodiimide hydrochloride, cyclized to obtain beta-lactam compound under the action of triphenylphosphine and diisopropyl azodicarboxylate, hydrolyzed by lithium hydroxide aqueous solution for ring opening, condensed with 3-trifluoromethyl-l, 2,4-triazolo [4,3-a ] pyrazine, and then protective groups are removed, thus obtaining sitagliptin.

The second generation synthetic route of sitagliptin is a chemical synthetic route which is developed by America Moshadong company and adopts chiral rhodium as a catalyst to construct a chiral center, and the route reduces the production cost compared with the prior route. Condensing 2,4, 5-trifluoro-phenylacetic acid with 2, 2-dimethyl-1, 3-dioxane-4, 6-diketone, condensing with 3-trifluoromethyl-1, 2,4-triazolo [4,3-a ] pyrazine to obtain (2Z) -4-oxo-4- [ 3-trifluoromethyl-5, 6-dihydro- [1,2,4] -triazolo [4,3-a ] pyrazine-7-8H-yl ] -1-2,4, 5-trifluorophenyl-butyl-2-ketone, reacting with ammonium acetate to obtain enamine, and reacting enamine with dimeric chloro l, 5-cyclooctadiene rhodium and (R) - (-) - [ (S) -2- [ di (4-trifluoromethylphenyl) phosphine ] ferrocenyl ] ethyl-2-tert-butyl And carrying out asymmetric hydrogenation reaction under the action of phosphine to obtain sitagliptin.

The third-generation synthetic route of sitagliptin is a novel green and environment-friendly biocatalytic synthetic route developed by improving the process and utilizing a method for constructing a chiral center by using mutant transaminase on the basis of a second-generation chemical synthetic method.

The chemical synthesis route of sitagliptin is complicated, the required reaction conditions are harsh, low temperature and long reaction time are required, and reagents used in part of the reaction route are expensive.

In order to solve the technical problems, the application provides a novel method for preparing sitagliptin, chiral amine compound is obtained by reductive amination of borohydride in the presence of chiral ligand, side reaction is reduced by activation of carboxyl by N-hydroxysuccinimide, high-yield and high-purity sitagliptin product is obtained, reaction raw materials are cheap and easy to obtain, the reaction process is easy to operate, the yield of each step is high, the product purity is high, the production cost is reduced, and the method is favorable for industrial production.

Disclosure of Invention

The invention aims to solve the technical problems that in the prior art, a sitagliptin reaction route is complicated, part of reaction conditions are harsh, the reaction route is long, raw materials are expensive, the yield is low, the product purity is not high, and the like.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

a synthetic method of sitagliptin comprises the following synthetic route:

the specific reaction process comprises the following steps:

adding compound I and NH in tetrahydrofuran under the protection of inert gas₂OBn, stirred at room temperature for 1-2 hours, then added with catalytic amount of [ (p-cymene) RuCl₂]₂And (R, S) -t-Butyl Josiphos, stirring for 0.5-1 hr, and adding ZnCl₂And NaBH₃CN, continuously stirring for 10-30 minutes, heating and refluxing, monitoring the reaction process by TLC, quenching excessive reducing agent by using saturated ammonium chloride solution after the reaction is finished, filtering, washing, and concentrating the organic phase under reduced pressure to obtain a compound II.

Wherein the inert gas is selected from nitrogen or argon; [ (p-cymene) RuCl₂]₂And (R, S) -t-Butyl Josiphos in a molar amount of 0.05-5% of compound I; ZnCl₂And NaBH₃CN is used in 1-5 times of the molar amount of the compound I.

And (3) carrying out palladium-carbon hydrogenation reduction reaction on the compound II in chloroform for 4-6 hours, filtering, washing with chloroform, adjusting the pH of the filtrate to 3-5 with hydrochloric acid, carrying out reflux reaction for 6-8 hours, adjusting the pH to 6.5-7.5 with sodium hydroxide solution, layering, adding anhydrous magnesium sulfate into the organic phase, drying overnight, and removing the solvent under reduced pressure to obtain a compound III.

And (2) taking DMF as a solvent, carrying out reflux reaction on the compound III and N-hydroxysuccinimide for 2-3 hours in the presence of a dehydrating agent, monitoring the reaction process by TLC, after the reaction is finished, carrying out reduced pressure concentration, and carrying out column chromatography purification to obtain a compound IV.

Wherein, the dehydrating agent is selected from EDC or DCC, and the molar dosage is 1-3 times of that of the compound III; the molar ratio of the compound III to the N-hydroxysuccinimide is 1: 1-3.

And (2) in tetrahydrofuran, in the presence of organic alkali, carrying out reflux reaction on the compound IV and 3-trifluoromethyl-1, 2,4-triazolo [4,3-a ] pyrazine for 0.5-1 h, monitoring the reaction process by TLC, after the reaction is finished, carrying out reduced pressure concentration, and purifying by column chromatography to obtain the sitagliptin product.

Wherein, the organic base is selected from one or more of triethylamine, trimethylamine, pyridine, picoline and DBU, and the molar amount of the organic base is 1 to 3 times of that of the compound IV; the molar ratio of the compound IV to the 3-trifluoromethyl-1, 2,4-triazolo [4,3-a ] pyrazine is 1: 1-2.

The invention has the beneficial effects that:

the invention provides a brand new synthetic route for preparing sitagliptin, the reaction route is obviously shortened, the adopted raw materials are cheaper and easily obtained, the reaction process is easy to operate, the yield of each step is high, the chiral selectivity of more than 99.9 percent of e.e. value is achieved, the reaction selectivity is stronger through activating carboxyl, byproducts are reduced, the purity of the obtained product is high, the production cost is reduced, and the industrial production is facilitated.

Drawings

Fig. 1 is a synthetic route for sitagliptin.

Detailed Description

The invention discloses a preparation method of sitagliptin, which can be realized by appropriately improving process parameters by taking the contents of the sitagliptin as reference. It is expressly intended that all such alterations and modifications which are obvious to those skilled in the art are deemed to be incorporated herein by reference, and that the techniques of the invention may be practiced and applied by those skilled in the art without departing from the spirit, scope and range of equivalents of the invention.

In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art.

In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description of the present invention is provided with reference to specific embodiments.

Example 1: preparation of Compounds of formula II

In 100mL of tetrahydrofuran, under nitrogen protection, 5.92g (24mmol) of compound I and 4.44g (36mmol) of NH are added₂OBn, stirred at RT for 1 hour, then 0.11g (0.18mmol) of [ (p-cymene) RuCl₂]₂And 0.049g (0.09mmol) of (R, S) -t-Butyl Josiphos, stirring was continued for 0.5 h, and finally 6.81g (50mmol) of ZnCl were added₂And 5.88g (94mmol) NaBH₃And CN, stirring for 20 minutes, heating and refluxing, monitoring the reaction progress by TLC, quenching excessive reducing agent by using an ammonium chloride saturated solution after the reaction is finished, filtering, washing with water, concentrating under reduced pressure by using an organic phase, and performing column chromatography to obtain the compound II6.25g (17.7mmol), wherein the yield is 74 percent and e.e.>99.9％。

¹H NMR(CHCl₃-d,400M)δ：7.32-7.45(m,5H),6.69(s,1H),6.65(s,1H),5.45(s, 3H),4.77(s,2H),4.35(d,2H),3.44(m,1H),2.69(d,2H)；¹³C NMR(CHCl₃-d,400M)δ: 173.1,157.8,147.1,145.2,136.5,132.1,128.9,127.6,127.1,125.6,123.9,118.5, 106.8,77.3,51.4,33.1,31.4,29.1；MS-ESI(m/z):354.12[M+H]⁺。

Example 2: preparation of Compounds of formula III

In a high pressure reactor, 5.31g (15mmol) of compound II was subjected to hydrogenation reduction reaction on palladium on carbon in 100mL of chloroform for 6 hours, filtered, washed with an appropriate amount of chloroform, the filtrate was transferred to a round bottom flask, pH was adjusted to 4 with hydrochloric acid, reflux reaction was carried out for 6 hours, pH was adjusted to 6.8 with sodium hydroxide solution, layers were separated, the organic phase was dried over anhydrous magnesium sulfate overnight, and the solvent was removed under reduced pressure to obtain 2.71g (11.6mmol) of compound III with a yield of 77%.

¹H NMR(CHCl₃-d,400M)δ：6.81(s,1H),6.65(s,1H),3.34(m,1H),2.92(d,2H), 2.34(d,2H)；¹³C NMR(CHCl₃-d,400M)δ:177.1,157.8,147.4,145.2,122.9,118.5, 106.8,48.3,46.6,37.1；MS-ESI(m/z):234.04[M+H]⁺。

Example 3: preparation of Compounds of formula IV

80mL of DMF was used as a solvent, 10.31g (50mmol) of DCC, 5.83g (25mmol) of Compound III and 2.31g (20mmol) of N-hydroxysuccinimide were added, and the mixture was refluxed for 2 hours, and the progress of the reaction was monitored by TLC, after completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain Compound IV7.86g (23.8mmol) in 95% yield.

¹H NMR(CHCl₃-d,400M)δ：6.85(s,1H),6.67(s,1H),3.39(m,1H),2.95(d,2H), 2.64(m,4H),2.38(d,2H)；¹³C NMR(CHCl₃-d,400M)δ:177.1,169.6,157.7,147.5, 145.3,122.7,118.7,106.6,48.2,46.5,37.2,25.6；MS-ESI(m/z):331.06[M+H]⁺。

Example 4: preparation of sitagliptin

4.11g (41mmol) of triethylamine, 6.60g (20mmol) of compound IV and 4.81g (25mmol) of 3-trifluoromethyl-1, 2,4-triazolo [4,3-a ] pyrazine are added into 100mL of tetrahydrofuran for reflux reaction for 1 hour, the reaction progress is monitored by TLC, after the reaction is finished, the mixture is concentrated under reduced pressure and purified by column chromatography, and then 7.90g (19.4mmol) of sitagliptin is obtained, the yield is 97%, and the HPLC purity is 99.88%.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (4)

1. The preparation method of sitagliptin is characterized by comprising the following synthetic route:

the method specifically comprises the following steps:

adding compound I and NH in tetrahydrofuran under the protection of inert gas₂OBn, stirred at room temperature for 1-2 hours, then added with catalytic amount of [ (p-cymene) RuCl₂]₂And (R, S) -t-Butyl Josiphos, stirring for 0.5-1 hr, and adding ZnCl₂And NaBH₃CN, continuously stirring for 10-30 minutes, heating and refluxing, monitoring the reaction process by TLC, quenching excessive reducing agent by using an ammonium chloride saturated solution after the reaction is finished, filtering, washing, and concentrating the organic phase under reduced pressure to obtain a compound II;

carrying out hydrogenation reduction reaction on the compound II in chloroform for 4-6 hours by using palladium-carbon, filtering, washing by using chloroform, adjusting the pH of the filtrate to 3-5 by using hydrochloric acid, carrying out reflux reaction for 6-8 hours, adjusting the pH of the filtrate to 6.5-7.5 by using sodium hydroxide solution, layering, adding anhydrous magnesium sulfate into an organic phase, drying overnight, and removing the solvent under reduced pressure to obtain a compound III;

performing reflux reaction on the compound III and N-hydroxysuccinimide for 2-3 hours by using DMF as a solvent in the presence of a dehydrating agent, monitoring the reaction process by TLC, after the reaction is finished, concentrating under reduced pressure, and purifying by column chromatography to obtain a compound IV;

and (2) in tetrahydrofuran, in the presence of organic alkali, carrying out reflux reaction on the compound IV and 3-trifluoromethyl-1, 2,4-triazolo [4,3-a ] pyrazine for 0.5-1 h, monitoring the reaction process by TLC, after the reaction is finished, carrying out reduced pressure concentration, and purifying by column chromatography to obtain the sitagliptin product.

2. The process for the preparation of sitagliptin according to claim 1, characterized in that: the inert gas is selected from nitrogen or argon; [ (p-cymene) RuCl₂]₂And (R, S) -t-Butyl Josiphos in a molar amount of 0.05-5% of compound I; ZnCl₂And NaBH₃CN is used in 1-5 times of the molar amount of the compound I.

3. The process for the preparation of sitagliptin according to claim 1, characterized in that: the dehydrating agent is selected from EDC or DCC, and the molar dosage is 1-3 times of that of the compound III; the molar ratio of the compound III to the N-hydroxysuccinimide is 1: 1-3.

4. The process for the preparation of sitagliptin according to claim 1, characterized in that: the organic base is selected from one or more of triethylamine, trimethylamine, pyridine, picoline and DBU, and the molar amount of the organic base is 1-3 times of that of the compound IV; the molar ratio of the compound IV to the 3-trifluoromethyl-1, 2,4-triazolo [4,3-a ] pyrazine is 1: 1-2.

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